Study on the Effective Dose and Safety of Esketamine in Hysteroscopic Surgery Under Monitored Anesthesia Care
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 95
- 试验地点
- 1
- 主要终点
- Cervical dilation-induced somatic responses
研究概览
简要总结
Cervical dilation-induced somatic responses remain a critical challenge in ambulatory hysteroscopic surgery. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exhibits unique analgesic and sedative properties that may enhance perioperative somatic response inhibition. However, the effective dose of esketamine under dexmedetomidine-remifentanil based monitored anesthesia care (MAC) during ambulatory hysteroscopic surgery remains to be determined. This prospective dose-finding study aimed to establish the median effective dose (ED50) and 95% effective dose (ED95) of esketamine for cervical response suppression. Afterwards, the investigators will conduct an RCT study to evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.
详细描述
This research will be divided into two stages. (i) In Phase one, a prospective dose discovery study using the Dixon sequential method will be conducted, aiming to determine the median effective dose (ED50) and 95% effective dose (ED95) of esketamine in inhibiting cervical response. Esketamine will be initiated by intravenous infusion at 0.3 mg∙kg-1, followed by somatic response based on cervical dilation (positive: any exercise; negative: no movement). Dose adjustment will be carried out, with a dose fluctuation step of 0.02 mg∙kg-1 up and down. All patients will receive a standardized anesthesia regimen, including continuous infusion of remifentanil at a dose of 5 μg∙kg∙h-1, combined with dexmedetomidine (infusion at a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance infusion at 0.4 μg∙kg-1∙h-1). The test will continue until six cross-pairings are obtained. Probabilistic regression analysis will be used to calculate the ED50 and ED95 of esketamine with a 95% confidence interval.
(ii) The investigators will conduct a single-center, randomized, double-blind controlled trial in Phase Two to evaluate the safety of the esketamine ED95 dose under the monitoring anesthesia care program based on the incidence of respiratory depression. The intervention group will be injected with the dose of esketamine ED95; the control group will be injected with remifentanil 1μg∙kg-1. Both groups of patients will receive the same sedation regimen, namely remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (pumped at a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance pumping at 0.4 μg∙kg-1∙h-1). Intravenous injection of 100 mg of flurbiprofen axetil for auxiliary analgesia. Intravenous injection of 4 mg of ondansetron to prevent nausea and vomiting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Supportive Care
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Aged 18 - 55 years;
- •ASA physical status Ⅰ or Ⅱ;
- •Body mass index (BMI) 18 - 28 kg∙m-2;
- •Scheduled for elective diagnostic/therapeutic hysteroscopy.
排除标准
- •(i) Pharmacological contraindications:
- •Known hypersensitivity to study medications (esketamine, remifentanil, dexmedetomidine);
- •Opioid or benzodiazepine medications dependence;
- •Analgesic/psychotropic medication use within 48 hours preoperatively;
- •Participation in any other drug clinical trial within the preceding three months.
- •(ii) Comorbidities:
- •Significant cardiopulmonary dysfunction (NYHA III-IV, FEV₁/FVC <70%);
- •Hepatic impairment (Child-Pugh B/C);
- •Uncontrolled hypertension, intracranial hypertension, intraocular hypertension or hyperthyroidism;
- •Neurological/psychiatric conditions (epilepsy, schizophrenia, depression);
- •Active gastroesophageal reflux disease (GERD-Q score ≥8). (iii) Airway/Perioperative Risks:
- •Anticipated difficult airway (Mallampati III-IV, thyromental distance <6 cm) or airway stenosis;
- •Non-fasted status (solids <8h, clear fluids <2h preoperatively).
研究组 & 干预措施
Determine the ED50 and ED95 of esketamine by Dixon's up-and-down method
According to Dixon's up-and-down sequential design, esketamine will be initiated at 0.3 mg∙kg-1 intravenously, followed by dose adjustments (0.02 mg∙kg-1 increments/decrements) based on somatic responses to cervical dilation (positive: any movement; negative: no movement). The tests will continue until six crossover pairs are achieved.
干预措施: Determine the ED50 and ED95 of esketamine (Drug)
Evaluate the safety of the dose of esketamine ED95 by the incidence of respiratory depression
The intervention group will be injected with the dose of esketamine ED95; the control group will be injected with remifentanil 1μg∙kg-1. Both groups of patients will receive the same Monitoring Anesthesia Care (MAC) regimen, namely, remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 0.4 μg∙kg-1∙h-1). Intravenous injection of 100 mg of flurbiprofen axetil for auxiliary analgesia. Intravenous injection of 4 mg of ondansetron to prevent nausea and vomiting. The study at this stage will evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.
干预措施: Intravenous the dose of esketamine ED95 (Drug)
Evaluate the safety of the dose of esketamine ED95 by the incidence of respiratory depression
The intervention group will be injected with the dose of esketamine ED95; the control group will be injected with remifentanil 1μg∙kg-1. Both groups of patients will receive the same Monitoring Anesthesia Care (MAC) regimen, namely, remifentanil will be continuously pumped at a rate of 5μg∙kg∙h-1 combined with dexmedetomidine (a loading dose of 0.6 μg∙kg-1 for 10 minutes, followed by maintenance dose of 0.4 μg∙kg-1∙h-1). Intravenous injection of 100 mg of flurbiprofen axetil for auxiliary analgesia. Intravenous injection of 4 mg of ondansetron to prevent nausea and vomiting. The study at this stage will evaluate the safety of the dose of esketamine ED95 through the incidence of respiratory depression.
干预措施: Intravenous remifentanil 1μg∙kg-1 (Drug)
结局指标
主要结局
Cervical dilation-induced somatic responses
时间窗: Day 1 (During the surgery at the first stage of the research)
Positive: Body movement or complaint of pain. Negative: No body movement or no reported pain. This scale will be administered during the surgery at the first stage of the research.
Incidence of respiratory depression
时间窗: Day 1 (T2-T6 of the second stage of the research)
The primary outcome is the incidence of respiratory depression, which is defined as SpO2 \<90% or EtCO2 \>55 mmHg. By comparing with the control group, evaluate the safety of ED95 of esketamine by the incidence of respiratory depression at T2-T6 of the second stage of the research. T2: 60 seconds after esketamine injection; T3: During vaginal disinfection; T4: During cervical dilation; T5: During intrauterine operations; T6: In the PACU.
次要结局
- HR(Day 1 (T1-T6 of the first and second stages of the research))
- MAP(Day 1 (T1-T6 of the first and second stages of the research))
- SPO2(Day 1 (T1-T6 of the first and second stages of the research))
- EtCO2(Day 1 (T2-T6 of the first and second stages of the research))
- Adverse events(Day 1 (T2-T9 of the first and second stages of the research))
- Duration of awakening(Day 1 of the first and second stages of the research)
- PACU time(Day 1 of the first and second stages of the research)
- RR(Day 1 (T1-T6 of the first and second stages of the research))
- NRS(Day 1 (T7-T9 of the first and second stages of the research))
- The need for remedial analgesia(Day 1 (T7-T9 of the first and second stages of the research))
- Induction duration(Day 1 of the first and second stages of the research)
- Discharge time(Day 1 of the first and second stages of the research)
- Success rate of anesthesia(Day 1 (T2-T5 of the second stage of the research))
- The satisfaction of gynecologists(Day 1 of the second stage of the research)
- The satisfaction of patients(Day 2 of the second stage of the research)
研究者
Lijuan Yan
Scientific Research Secretary of the Anesthesiology Department
The First Affiliated Hospital of Xiamen University